Inorganic, monovalent cations compete with agonists for the transmitter binding site of nicotinic acetylcholine receptors

Akk, Gustav; Auerbach, Anthony

doi:10.1016/s0006-3495(96)79834-x

Cited by 67 publications

(112 citation statements)

References 29 publications

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“…We simultaneously analyzed recordings obtained at multiple ACh concentrations (10-300 M) with the aim of representing all the states in Scheme 1 in the analysis. Rate constant estimates obtained for wild-type nAChR (F ϭ 2 in Table 3) agree with those previously reported for mouse nAChR (Akk and Auerbach, 1996;Wang et al, 1997;Salamone et al, 1999;Bouzat et al, 2000).…”

Section: Resultssupporting

confidence: 89%

Nicotinic Receptor M3 Transmembrane Domain: Position 8′ Contributes to Channel Gating

et al. 2002

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The nicotinic acetylcholine receptor (nAChR) is a pentamer of homologous subunits with composition ␣ 2 ␤⑀␦ in adult muscle. Each subunit contains four transmembrane domains (M1-M4). Position 8Ј of the M3 domain is phenylalanine in all heteromeric ␣ subunits, whereas it is a hydrophobic nonaromatic residue in non-␣ subunits. Given this peculiar conservation pattern, we studied its contribution to muscle nAChR activation by combining mutagenesis with single-channel kinetic analysis. Construction of nAChRs carrying different numbers of phenylalanine residues at 8Ј reveals that the mean open time decreases as a function of the number of phenylalanine residues. Thus, all subunits contribute through this position independently and additively to the channel closing rate. The impairment of channel opening increases when the number of phenylalanine residues at 8Ј increases from two (wild-type nAChR) to five. The gating equilibrium constant of the latter mutant nAChR is 13-fold lower than that of the wild-type nAChR. The replacement of ␣F8Ј, ␤L8Ј, ␦L8Ј, and ⑀V8Ј by a series of hydrophobic amino acids reveals that the structural bases of the observed kinetic effects are nonequivalent among subunits. In the ␣ subunit, hydrophobic amino acids at 8Ј lead to prolonged channel lifetimes, whereas they lead either to normal kinetics (␦ and ⑀ subunits) or impaired channel gating (␤ subunit) in the non-␣ subunits. The overall results indicate that 8Ј positions of the M3 domains of all subunits contribute to channel gating.

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Section: Resultssupporting

confidence: 89%

Nicotinic Receptor M3 Transmembrane Domain: Position 8′ Contributes to Channel Gating

et al. 2002

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“…The interaction between the immobilised TDAC ligand and the acetylcholine receptor, while being specific, is relatively easy to disrupt with an increasing NaCl gradient (160-320·mmol·l -1 NaCl; Fig.·3A). It has long been established that the binding of ligands to the acetylcholine receptor is sensitive to the presence of cations (Akk and Auerbach, 1996;Schmidt and Raftery, 1974). Therefore, it is perhaps not surprising that the receptor's interaction with the immobilised TDAC ligand is sensitive to the NaCl concentration.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic conservation of disulfide-linked, dimeric acetylcholine receptor pentamers in southern ocean electric rays

Tierney

Osborn

Milburn

et al. 2004

Journal of Experimental Biology

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Intact acetylcholine receptors have been purified on a novel affinity resin from three electric fish endemic to Australian waters. Their binding properties and morphology are compared with those of their northern hemisphere homolog, Torpedo marmorata. All four exhibit apparent dissociation constants, Kd, in the nanomolar range for the snake neurotoxin α-bungarotoxin and have a distinctive rosette-like appearance when viewed in negative stain under the electron microscope. Furthermore, these rosettes are paired, indicating that acetylcholine receptors from southern ocean electric fish exist as dimers, in the same fashion as their northern hemisphere counterparts. The cDNAs of the receptor's four subunits were sequenced from Hypnos monopterigium and the northern hemisphere counterpart, Torpedo marmorata, while cDNAs from only two subunits, α and δ, were able to be sequenced from Narcine tasmaniensis. The penultimate amino acid in the δ subunit of each of the newly sequenced fish species is a cysteine residue. Its conservation suggests that the mechanism for the observed dimerization of acetylcholine receptors is disulfide bond formation between the δ subunit of adjacent receptors, analogous to acetylcholine receptor dimers observed in other electric fish. It appears that this mechanism for receptor clustering is unique to acetylcholine receptors packed and organized in the specialized organs of electric fish. Alignment of the deduced protein sequences with the equivalent sequences from Torpedo californica and humans reveals a high degree of homology.

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“…Therefor, we examined the binding of the agonist analog tetramethylamine (TMA), which binds the nAChR with lower affinity (equilibrium binding affinity is Х0.5 mM; Akk and Auerbach, 1996).…”

Section: Downloaded Frommentioning

confidence: 99%

Lipid Composition Alters Drug Action at the Nicotinic Acetylcholine Receptor

Baenziger

Ryan²,

Goodreid³

et al. 2007

Mol Pharmacol

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We tested the hypothesis that membrane lipid composition influences drug action at membrane proteins by studying local anesthetic action at the nicotinic acetylcholine receptor (nAChR). Infrared difference spectra show that concentrations of tetracaine consistent with binding to the ion channel (Ͻ50 M) stabilize a resting-like state when the nAChR is reconstituted into phosphatidylcholine membranes containing the anionic lipid, phosphatidic acid, but have no effect on the nAChR reconstituted into membranes lacking phosphatidic acid, either in the presence or absence of cholesterol. Concentrations of tetracaine above 200 M lead to neurotransmitter site binding in all membranes. In the presence of phosphatidic acid, cholesterol, or both, neurotransmitter site binding leads to the formation of quaternary amine-aromatic interactions between tetracaine and binding site tyrosine/tryptophan residues and the stabilization of a desensitized state. One interpretation suggested by lipid partitioning studies is that phosphatidic acid enhances tetracaine action at the channel pore by increasing the partitioning of tetracaine into the lipid bilayer, thereby enhancing access to the transmembrane pore. However, subtle membrane-dependent variations in the vibrations of tyrosine and tryptophan residues, and agonist analog binding studies indicate that the structures of the agonist-bound neurotransmitter sites of the nAChR in membranes lacking both phosphatidic acid and cholesterol differ from the structures of the agonist-desensitized neurotransmitter sites in the presence of both lipids. Lipid action at the nAChR thus involves more than a simple modulation of the equilibrium between resting and desensitized states.

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Inorganic, monovalent cations compete with agonists for the transmitter binding site of nicotinic acetylcholine receptors

Cited by 67 publications

References 29 publications

Nicotinic Receptor M3 Transmembrane Domain: Position 8′ Contributes to Channel Gating

Nicotinic Receptor M3 Transmembrane Domain: Position 8′ Contributes to Channel Gating

Phylogenetic conservation of disulfide-linked, dimeric acetylcholine receptor pentamers in southern ocean electric rays

Lipid Composition Alters Drug Action at the Nicotinic Acetylcholine Receptor

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